Novel piperazine- and homopiperazine-monoalkanol esters and a process of production thereof

ABSTRACT

There is provided piperazine or homopiperazine-monoalkanol esters and salts thereof. These compounds are prepared by esterification of the corresponding alkanol compounds. 
     The novel compounds are characterized by therapeutic activity and specifically, analgetic, coronary vaso-dilative, anti-convulsant, and blood pressure-decreasing properties.

The present invention relates to a process of producing a piperazine- or homopiperazine-monoalkanol ester represented by the formula: ##EQU1## WHEREIN R is a phenyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, or a styryl group or a 2-, 3- or 4-pyridyl group which may be substituted with a lower alkoxy group; and n and m are 2 or 3, respectively, and a salt thereof.

According to the present invention, the compounds represented by the formula (I) above can be produced by esterification of a piperazine- or homopiperazine-monoalkanol represented by the formula: ##EQU2## WHEREIN N AND M EACH REPRESENTS 2 OR 3, OR A SALT THEREOF, WITH A BENZOIC ACID WHICH MAY BE SUBSTITUTED WITH A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP OR A HALOGEN ATOM, OR A CINNAMIC ACID OR A NICOTINIC ACID COMPOUND INCLUDING NICOTINIC ACID, ISONICOTINIC ACID AND PICOLINIC ACID WHICH MAY BE SUBSTITUTED WITH A LOWER ALKOXY GROUP.

The esterification in accordance with the present invention proceeds successfully in the presence of a dehydrating agent. Specific examples of suitable dehydrating agents include hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, N,N dicyclohexylcarbodiimide, etc. Among those, p-toluene sulfonic acid is most preferred. Any solvent can be employed in the esterification in accordance with the present invention unless the solvents prevent the reaction. Typical examples of suitable solvents are benzene, toluene, xylene, dioxane, chloroform, tetrahydrofuran, etc., preferably, benzene or dioxane is employed. The preferred reaction temperature is, in general, above room temperature, more preferably, near the boiling point of the solvent employed.

The product (I) produced in accordance with the present invention can be converted into the corresponding salt using an inorganic or organic acid in a conventional manner. Typical examples of inorganic acids include hydrohalic acids (hydrochloric acid, hydrobromic acid), sulfuric acid, phosphoric acid, etc. The organic acids which can be employed in the present invention are typified by lactic acid, maleic acid, succinic acid, tartaric acid, salicylic acid, oxalic acid, citric acid, benzoic acid, etc.

The novel compounds (I) in accordance with the present invention exhibits analgetic, coronary vasodilative, anticonvulsant, blood pressure decreasing properties, and such compounds are particularly useful as therapeutic agents in treating circulatory diseases and are further useful as intermediates in preparing therapeutic agents.

The following examples are merely illustrative and are not to be considered as limiting the invention.

EXAMPLE 1

In 150 ml of absolute benzene there were dissolved 2.6 g of 1-piperazineethanol, 5.5 g of 2,3,4-trimethoxybenzoic acid and 19 g of p-toluene sulfonic acid. The solution was heated for 15 hours to reflux while removing the formed water. After the reaction liquid was cooled, the reaction liquid was washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After washing the aqueous layer with ether, the system was rendered alkaline with potassium carbonate followed by extraction with ether. The ethereal layer was dehydrated with a Glauber's salt and then the ether was removed by distillation. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was treated in a conventional manner to convert the product into the maleic acid salt thereof. Upon crystallization from ethanol, 1-piperazineethanol 2,3,4-trimethoxybenzoate maleate was obtained exhibiting a melting point of 140°-141°C. The Yield was 46%.

Elemental Analysis: as C₁₆ H₂₄ N₂ O₅.2 (C₄ H₄ O₄).H₂ O; Calculated: C:50.49; H:5.98; N:5.00, Found: C:50.37; H:5.97; N:4.88.

EXAMPLE 2

In 150 ml of absolute dioxane there were dissolved 2.88 g of 1-piperazinepropanol, 3.64 g of p-fluorobenzoic acid and 19 g of p-toluene sulfonic acid. While removing the formed water, the solution was heated for 16 hours to reflux. After the dioxane was removed from the reaction liquid, ether was added to the residue. The system was extracted with 10% hydrochloric acid. The aqueous layer was rendered alkaline using potassium carbonate and then extracted with ether. The ethereal layer was dehydrated with a Glauber's salt. The ether was removed from the system by distillation. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was converted into the hydrochloride thereof in accordance with a conventional manner. Upon recrystallization from ethanol, 1-piperazinepropanol P-fluorobenzoate hydrochloride was obtained exhibiting a melting point of 196°-199°C. The Yield was 56%.

Elemental Analysis: as C₁₄ H₁₉ N₂ O₂ F.2HCl.H₂ O; Calculated: C: 47.07; H: 6.49; N: 7.84; Found: C: 46.83; H: 6.56; N: 7.84.

EXAMPLE 3

In 150 ml of absolute benzene there were dissolved 1.44 g of 1-homopiperazineethanol and 9.5 g of p-toluene sulfonic acid. To the resulting solution, 2.75 g of 2,3,4-trimethoxybenzoic acid was added. The system was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% HCl. After the aqueous layer was washed with ether and then rendered alkaline with potassium carbonate, followed by extraction with ether. After the ethereal layer was dehydrated with a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. The liquid was converted into the maleic acid salt thereof in accordance with a conventional manner. Upon recrystallization from ethanol, 1-homopiperazineethanol 2,3,4-trimethoxybenzoate maleate was obtained having a melting point of 112°-113°C. The Yield was 59%.

Elemental Analysis: as C₁₇ H₂₆ N₂ O₅.2(C₄ H₄ O₄).H₂ O; Calculated: C: 51.02; H: 6.17; N: 4.76; Found: C: 50.91; H: 6.25; N: 4.71.

EXAMPLE 4

In 150 ml of absolute benzene there were dissolved 2.88 g of 1-piperazinepropanol, 3.2 g of isonicotinic acid and 30.4 g of p-toluene sulfonic acid. The resulting solution was heated for 15 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate and then extracted with ether. After the ethereal layer was dehydrated with a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. This liquid was converted to the hydrochloride thereof in accordance with a conventional manner. It was recrystallized from ethanol to give 1-piperazinepropanol isonicotinate hydrochloride. The melting point of the product was 201°-202°C. The Yield was 66%.

Elemental Analysis: as C₁₃ H₁₉ N₃ O₂.2 HCl.H.sub. 2 O; Calculated: C: 45.89; H: 6.81; N: 12.35; Found: C: 45.75; H: 6.92; N: 12.31.

EXAMPLE 5

In 150 ml of absolute benzene there were dissolved 3.04 g of 1-homopiperazinepropanol, 2.85 g of picolinic acid and 2.73 g of p-toluene sulfonic acid. The solution was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. The aqueous layer was washed with ether, then rendered alkaline with potassium carbonate followed by extraction with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was converted into the maleic acid salt thereof in accordance with a conventional manner. Upon recrystallization of the maleic acid salt from ethanol, 1-homopiperazinepropanol picolinate maleate was obtained having a melting point of 105°-107°C. The Yield was 47%.

Elemental Analysis: as C₁₄ H₂₁ N₃ O₂.2 C₄ H₄ O₄.H₂ O; Calculated: C: 51.46; H: 6.09; N: 8.18, Found: C: 51.30; H: 6.22; N: 8.14.

EXAMPLE 6

In 150 ml of absolute benzene there were dissolved 1.95 g of 1-piperazineethanol and 14.2 g of p-toluene sulfonic acid. To the solution 2.89 g of cinnamic acid was added. The system was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline followed by extraction with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to give a colorless transparent liquid. The liquid was converted into the hydrochloride thereof. Upon recrystallization from ethanol, 1-piperazineethanol cinnamate hydrochloride was obtained. The melting point of the product was 184°- 187°C. The yield was 53%.

Elemental Analysis: as C₁₅ H₂₀ N₂ O₂.2 HCl.H₂ O; Calculated: C: 48.66; H: 6.53; N: 7.56; Found: C: 48.61; H: 6.60; N: 7.48.

EXAMPLE 7

In 1.50 ml of absolute benzene there were dissolved 1.58 g of 1-homopiperazinepropanol, 3.09 g of 2,3,4-trimethoxycinnamic acid and 9.5 g of p-toluene sulfonic acid. The solution was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate to extract with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. The liquid was converted into the oxalate thereof in accordance with conventional manner. Upon recrystallization from methanol, 1-homopiperazinepropanol 2,3,4-trimethoxycinnamate oxalate was obtained having a melting point of 156°-158°C. The yield was 48%.

Elemental Analysis: as C₂₀ H₂₈ N₂ O₅.2 C₂ H₂ O₄.H₂ O; Calculated: C: 50.17; H: 5.97; N: 4.88; Found: C: 50.03; H: 6.18; N: 4.75.

The following compounds shown in the table below were obtained in a similar manner using the procedure of Example 1 - Example 7.

                                      TABLE                                        __________________________________________________________________________     No.  R                     n m Salt    Melting Point(°C)                __________________________________________________________________________     1.                         2 2 Maleate 150-151.5                               2.   "                     3 2 "       139-141                                 3.   "                     2 3 "       156.5-158.5                             4.   "                     3 3 "       146-148                                 5.                         2 3 "       141-143                                 6.   "                     3 3 "       144.5-145.5                             7.                         2 3 Hydrochloride                                                                          204-206                                 8.   "                     3 3 Maleate 154-156                                 9.                         2 3 Hydrochloride                                                                          180-183                                 10.  "                     3 3 Maleate 146-148                                 11.                        2 3 "       149-150                                 12.  "                     3 3 "       122-123.5                               13.                        3 3 Hydrochloride                                                                          175-177                                 14.                        2 3 "       178.5-181                               15.  "                     3 3 Maleate 133-134                                 16.                        2 2 "       127-128                                 17.  "                     2 3 "       138-140                                 18.                        2 2 "       137-138                                 19.  "                     2 3 "       158-159                                 20.  "                     3 2 "       119-121                                 21.  "                     3 3 "       148-149                                 22.                        2 2 "       146-147                                 23.  "                     3 2 "       112-115                                 24.  "                     3 3 "       127-130                                 25.                        2 3 Hydrochloride                                                                          198-200                                 26.  "                     3 2 Maleate 138-141                                 27.  "                     3 3 "       139-140                                 28.                        2 2 "       127-128                                 29.  "                     2 3 "       134-135                                 30.  "                     3 2 Oxalate 150-151                                 31.  "                     3 3 Maleate 108-110                                 32.                        2 2 "       123-124.5                               33.  "                     2 3 "       134-135.5                               34.  "                     3 2 Oxalate 158-161                                 __________________________________________________________________________

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. 

What is claimed is:
 1. A compound represented by the formula: ##EQU3## wherein R is a methyl or ethyl group and n is 2 or 3 and m is 3, and salts thereof.
 2. A compound represented by the formula: ##SPC1##
 3. A compound represented by the formula: ##SPC2##
 4. A compound represented by the formula: ##SPC3##and salts thereof. 